How would you like to share?

When people learn that they carry a gene for a fatal neurological disorder, they fear not just for themselves, but for their children who might inherit the same condition. Some vow never to have biological children. This was the case for Amanda Kalinsky, who at the age of 26 found out that she carried the gene for Gerstmann-Sträussler-Scheinker (GSS) syndrome, an autosomal-dominant prion disease. She had watched her father, uncle, grandfather, and great-aunt die slow and painful deaths from GSS, and she swore she would not saddle her future children with the disease. Then a genetic counselor told her about preimplantation genetic diagnosis (PGD), in which doctors test embryos conceived in vitro for a disease gene and implant only those that are free of it. “I’d never heard of it before; my husband is a physician and he’d never heard about it before,” Kalinsky said.

Amanda Kalinsky with her husband. Image courtesy of Amanda Kalinsky.

The counselor laid out the pros and cons, which included the warning that the process would be long, expensive, and arduous. Kalinsky and her husband thought about it for a couple of months before they decided to try it. “Genetic counseling really helped me,” Kalinsky said. “It should be mandatory for families considering this.” The Kalinskys now have 3-year-old twins and a year-old boy, who will never have to worry about having GSS. The New York Times told the Kalinskys' story on Feb. 3, and the case was written up in JAMA Neurology (see Tur-Kaspa et al., 2014).

Kalinsky has no doubt about her choice. “I would do it a million times over. When you get a diagnosis like this, you feel helpless. This is a way of fighting back and stopping the disease from passing to the next generation,” she told Alzforum.

With the increasing availability of PGD, more families will soon face the same choice the Kalinskys did. While many are intrigued by the promise of pruning fatal genes out of their family tree, they have to weigh this benefit against the procedure’s difficulties. This story lays out issues families confront as they decide what to do.

The Kalinsky children. Image courtesy of Amanda Kalinsky.

Costs and Stress Loom Large
The price tag presents a barrier to most families. In the United States, IVF for fertile couples is typically not covered by insurance, except in Massachusetts and Illinois. The cost of IVF and PGD varies by state. In Madison, Wisconsin, genetic counselor Margo Grady at Generations Fertility Care estimated the out-of-pocket price of one IVF cycle at about $12,000, and PGD adds another $3,000. Grady noted that she often gets insurers to cover the PGD portion, but not IVF. In New York City, IVF plus PGD runs about $25,000, said genetic counselor Jill Goldman at Columbia University. Since not all IVF cycles lead to a pregnancy, the expense can mount quickly. In Europe, the procedure is more likely to be covered by insurance, but it depends on the country. In Spain, Denmark, and the United Kingdom, PGD is covered only at public clinics; in much of Eastern Europe, it is not covered at all (see 2010 report by the European Society of Human Reproduction and Embryology PGD Consortium).

Several genetic counselors told Alzforum that cost is the primary deterrent. Grady said many couples initially express interest, but quickly bow out when they hear the price. Fewer than 5 percent of couples she speaks with go on to do it. In Massachusetts, where the procedure is covered, rates are much higher. Irene Souter, director of the PGD program at Massachusetts General Hospital Fertility Center, estimated that about half of the Huntington’s disease families her clinic counsels about the procedure eventually try it.

Beyond the financial burden, the invasive nature of PGD—and IVF in general—discourages some families. In IVF, women must take hormones and other drugs to stimulate the maturation of multiple eggs and prepare the uterus for a pregnancy, then their eggs must be harvested from their ovaries with a needle. There is no study that shows IVF has a lasting negative impact on the body, but subjectively women perceive it as quite grueling. Kalinsky said the hormones pitched her into huge emotional swings. “I went a little bit crazy,” she said. That ended once she stopped the treatment.

Human oocyte next to holding pipette (left) and being fertilized.

Some families are loath to “medicalize” their family planning. One young man whose father has the presenilin 1 gene told Alzforum, “I was happy to hear [PGD] was a possibility, but it definitely adds some strain to know that this is the way I’m going to have to approach a sacred thing such as having a baby. That it has to be planned out in advance and done in such a responsible way.”

Genetic counselors also caution families that, like any medical test, embryo testing carries a small chance for misdiagnosis. Carrie Koval, a genetic counselor at New York-Presbyterian Hospital, said she tells patients that the procedure dramatically cuts the risk that an embryo will carry a dominant gene, from 50 percent to about 2 percent. ESHRE data from 1997 to 2007 report a lower misdiagnosis risk, of about 0.5 percent (see Harper et al., 2012). Counselors suggest that if families want to be absolutely certain they won’t pass on a disease gene, they should get prenatal testing as well.

The Right Not To Know:Non-Disclosure PGD
Many people at risk of an inherited neurological disease do not want to know whether they have the gene. Goldman estimated that fewer than one in five people at risk for HD or early onset AD want to be tested. Most fertility clinics offer “non-disclosure PGD,” where clinic personnel withhold gene status from the prospective parents. To avoid leaking any clues, doctors do not tell the family how many eggs were retrieved or fertilized, or what percent were healthy. They perform IVF regardless of whether the at-risk parent carries the gene, hence that parent need not undergo predictive genetic testing as a prerequisite for PGD.

Non-disclosure PGD requires specialized protocols and attention to detail, Grady told Alzforum. She recommends that interested couples select a clinic that does the procedure regularly. A recent publication spells out recommended best practices for this method (see Tur-Kaspa, 2012).

Some clinics also offer a variation called exclusion testing, in which even clinic personnel do not find out whether the at-risk parent carries the gene. Instead, geneticists analyze markers from the region of the chromosome around the disease gene, and select only embryos that inherited those markers from the unaffected grandparent of the parent at risk. This option requires DNA testing of the grandparents, and also means that some healthy embryos with the normal gene from the affected grandparent would be discarded.

While there are no exact figures for how many couples choose non-disclosure or exclusion testing, Koval estimates that a quarter of the Huntington’s families she sees opt to be tested. Data from Europe indicate that about one-third of couples at risk for HD chose this option between 1995 and 2008 (see Van Rij et al., 2012).

The decision to know or not is highly personal. Jennifer Leyton, who watched her mother die from Huntington’s, chose not to learn her status when she got pregnant through PGD. “I just wanted to live my life,” she told Alzforum. Kalinsky made the opposite decision. “For me, living in the unknown is worse than living in the known,” she said. But she believes that the availability of non-disclosure PGD represents a wonderful option for families. “Knowing your results is a life-changing thing, and it’s not for everybody,” she said.

On average, about half the couples who choose non-disclosure PGD and IVF for dominant diseases do not carry the disease gene. For this reason, some countries in Europe, including the Netherlands, have balked at covering this procedure (see Asscher and Koops, 2010).

Ethics of PGD
In Europe, regulations on the use of PGD span the gamut. For example, Spain puts few restrictions on use; other countries, such as France and Germany, allow the procedure only for screening against severe genetic diseases; and a few, including Austria, Lithuania, and Latvia, ban it. Sex selection is forbidden throughout the European Union, but nonetheless about 2 percent of reported PGD cycles are done for this purpose, according to ESHRE data.

In the United States, the American Society for Reproductive Medicine has issued guidelines that support the procedure for severe, untreatable adult-onset conditions such as HD. The guidelines also recommend that PGD be allowed for less severe disorders, or genes that are not fully penetrant such as the breast cancer gene BRCA1. ASRM discourages the use of PGD for selecting a child’s sex. However, these guidelines are not binding. “There are no laws or regulations determining who may use PGD for what purpose,” Eleanor Nicoll at ASRM wrote Alzforum. For example, some U.S. clinics do offer sex selection for the purpose of balancing genders within a family.

In the absence of regulation, individual clinics are left to make their own decisions. “Anything that physicians are uncomfortable with we discuss as a group, and it goes through our ethics board,” Grady said. Her clinic has performed PGD to screen for risk genes of adult-onset illnesses such as BRCA1. “Generally, if it’s a serious disease, we welcome talking to people and setting up this process,” she said.

Some ethicists have raised questions about the use of the technology for adult-onset diseases. In 2002, when a woman who carried the V717L APP mutation first used PGD to conceive healthy children, some asked whether genetic technology should be used to help people who may not live to see their children reach adulthood become parents (see Towner and Loewy, 2002; 2002 AP news story). Others are troubled by the fact that embryos carrying a disease gene are discarded, albeit within a week of fertilization. Clinicians and counselors Alzforum spoke with believe this choice has to be left up to families. “I don’t think we can make that decision for them. Families with all kinds of diseases want to have children and do so successfully. They do need to plan for it and build their support system,” Goldman said.

Clinicians who have seen the devastation these diseases wreak on families believe the good outweighs the bad. “We’re not saying PGD should be done for sex selection or cosmetic traits or intelligence,” said Murali Doraiswamy at Duke University, Durham, North Carolina. “We are focusing on the fact that this technique is available for serious brain disorders that are inherited and often fatal. Every mother wants to give birth to a child who has the best chance at life.”

For couples from religious backgrounds, the choice may be wrenching. “To me, discarding embryos would be akin to abortion,” said one man whose father has the presenilin 2 gene. Nonetheless, he said if he had known about PGD before he had his children, he and his wife would have considered it. “We would have had to pray and talk to our pastor about it, but it would have been nice to have that option. Early onset Alzheimer’s is a terrible way to die.”

Families who have been through PGD say they struggled with the decision to discard affected embryos, but found it preferable to having to terminate a pregnancy. Jeff Carroll is a Huntington’s researcher at Western Washington University, Bellingham, who himself carries the gene for the disorder. He and his wife used PGD to have their twin boy and girl, who just turned eight. When they went through the procedure in 2005, PGD was rarely offered commercially, and methods were less refined than they are now. Doctors suggested that instead of PGD, the Carrolls use prenatal diagnosis such as chorionic villi sampling or amniocentesis and terminate an affected pregnancy. “We were uncomfortable with that,” Carroll told Alzforum.

He hopes that more families take up PGD to eliminate disease genes. “I’m glad I’m here. I’m glad that people of a previous generation had kids and carried on,” Carroll told Alzforum. “But we are a generation where this technology exists. It isn’t a cure for the generation alive today, but it’s a cure for the next generation. I think we owe it to them to use it as much as we can.”—Madolyn Bowman Rogers.